The current technical ability to microsurgically anastomose blood vessels ranging in diameter from 0.5 to 2 mm has made possible a wide variety of microvascular surgical procedures including digital replantations, composite tissue grafts, and free flap transfers. Despite the almost routine nature with which small blood vessels are anastomosed, a significant failure rate continues to occur due to postoperative vascular occlusion. Establishing and maintaining vascular patency is particularly difficult with regard to anastomosis of small veins because of the increased technical difficulty, modest venous blood flow favoring postoperative thrombosis, and the tendency for prolonged venospasm to occur. [Hayhurst, J. W., and O'Brien, B. McC, An experimental study of microvascular technique, patency rates and related factors. Brit. J. Plast. Surg. 28:128, 1975]. Venous thrombosis after anastomosis is primarily caused by platelet aggregation and the formation of an occluding platelet thrombus leading to vascular stasis, simultaneous activation of the coagulation cascade, and the formation of a permanent fibrin clot. [Hardisty, R. M., Disorders of platelet function. Brit. Med. Bull. 33:207, 1977]. If the formation of the initial platelet thrombus could be decreased or prevented, patency rates would theoretically be improved.
Emerging knowledge concerning the maintenance of vascular homeostasis under normal, pathologic, and traumatically altered vascular conditions increasingly demonstrates a key role of endogenous prostacyclin, an effective vasodilator and the most potent inhibitor of platelet aggregation yet discovered. [Moncada, S., Gryglewski, R., Bunting, S., and Vane, J. R., An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263:663, 1976; Ubatuba, F. B., Moncada, S., and Vane, J. R., The effect of prostacyclin (PGI.sub.2) on platelet behavior. Thrombus formation in vivo and bleeding time. Thromb. Haemost. 41:425, 1979]. Prostacyclin, synthesized from precursors within the vessel wall by the endothelium, maintains vascular tone and protects the vessel wall against deposition of platelet aggregates. [Kaley, G., The role of prostaglandins in vascular homeostasis. Fed. Proc. 35:2358, 1976; Bourgain, R. H., Inhibition of PGI.sub.2 (prostacyclin) synthesis in the arterial wall enhances the formation of white platelet thrombi in vivo. Haemostasis 7:252-255, 1978].
The enzyme necessary for prostacyclin synthesis is most abundant within the intima and progressively decreases in concentration toward the adventitia. In contrast, proaggregating activity, due primarily to collagen within the vessel wall, increases toward the adventitia. The blood vessel wall, therefore, exhibits a functional polarity, the endothelial lining being anti-aggregatory and the outer layers progressively more thrombogenic. [Moncada, S., and Amezcua, J. L., Prostacyclin, thromboxane A.sub.2 interactions in haemostasis and thrombosis. Haemost. 8:252, 1979; Moncada, S., Herman, A. G., Higgs, E. A., and Vane, J. R., Differential formation of prostacyclin (PGX or PGI.sub.2) by layers of the arterial wall. An explanation for the antithrombotic properties of vascular endothelium. Thromb. Res. 11:323, 1977].
Following vascular trauma and disruption of the endothelium, exposure of the underlying collagenous tissue leads to platelet activation and synthesis of thromboxane, a potent platelet aggregant and vasoconstrictor. The proaggregant activity of the collagenous vessel wall and platelet-derived thromboxane is normally balanced by the antagonistic effects of vessel wall-generated prostacyclin. The degree of vascular injury is therefore an important determinant of the ensuing vascular response. When vascular injury is slight, the normal equilibrium between prostacyclin and thromboxane is temporarily shifted toward thromboxane production leading to platelet aggregation and the formation of a transient hemostatic platelet plug sufficient to arrest hemorrhage but prevented, by endogenous prostacyclin, from enlarging intraluminally and causing vascular occlusion. When vascular trauma is severe, extensive exposure of platelets to collagenous vessel wall structures generates a major shift toward thromboxane synthesis and the simultaneous activation of the vascular coagulation cascade which may overwhelm the antagonistic effects of prostacyclin. The resulting wide-spread platelet aggregation, vasoconstriction, fibrin formation, and thrombosis leads to permanent vascular occlusion.
Because of its ability to inhibit platelet aggregation and induce vasodilation, prostacyclin is an attractive candidate as an antithrombotic agent. Used topically in an irrigant solution, prostacyclin has been shown to be effective in improving patency rates following arterial and venous microvascular anastomosis in the rat. [Leung, P. C., Chan, M. Y., and Roberts, M. B., The use of prostaglandins as local antithrombotic agents in microvascular surgery. Brit. J. Plast. Surg. 34:38, 1981; Emerson, D. J. M., Patel, C. B., Krishna, B. V., and Sykes, P. J., The use of prostacyclin in preventing occlusion of microvascular anastomoses by platelet thrombus: an experimental study in rats. Brit. J. Plast. Surg. 34:35, 1981]. However, topical application of prostacyclin to the adventitial surface of blood vessels requires its uptake by and penetration through the blood vessel wall in order to exert its effects.